Preparation of steroid alcohols



Patented Feb. 6, 19 51 PREPARATION or STEROID ALCOHOLS Robert H. Levin, A. Vern McIntosh, Jr'., and George B. Spero, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich., at corporation of Michigan No Drawing. Application October 2, 1947, Serial No. 777,576

12 Claims.

The present invention relates to steroid primary alcohols and to a method for the production thereof. The invention is more specifically concerned with certain steroid alcohols of the formula:

' P(CH2)n-CH2OH wherein P represents a pregnane nucleus attached to the side-chainat the 20 position, and n is selected from zero, one, and two, and with a -method for the preparation thereof from steroid thioesters of the formula:

wherein P and n have the values given for the desired alcohol and R is a thioalcohol residue.

It is an object of the present invention to provide novel primary steroid alcohols containing the pregnane nucleus and having a side-chain atthe position. These novel alcohols, containing acyloxy groups in the pregnane nucleus, have been unobtainable previously, as previous methods of alcohol preparation have involved the concomitant saponification or hydrolysis of the nuclear acyloxy groups. A further object of the invention is the provision of a process for the production of the said alcohols from thioesters having aside-chain containing the same number of carbon atoms. invention will become apparent hereinafter.

Members of the new group of compounds have been prepared, isolated, and found to be 'valuthioesters of desoxycholic acid, of the formula:

Other objects of the able intermediates in the preparation of more complex organic molecules, including certain hormones. 1

Among the thio esters which'may be employed as suitable starting materials for the preparation of the steroid alcohols are thioester derivatives of steroid acids, e. g., cholanic acid, of the formula:

1310 oH-oHr-oHr -sii thioester derivatives of ch01en1c acid, of the formula:

HaC

aC OH:

HO OH and thioesters of tetrahydroxycholanic acid, of the formula:

Esq CHI 7 0 no n-cm-om-JL-sn wherein R is an alcohol residue. Likewise, other I thioesters of unsaturated bile acids, such as B-hydroxy-(delta 5) -cholenic, 3,11-dihydroxy- (delta 5) -cholenic, and 3-hydroxy-(delta 5,7)

choladienic acids, are suitable starting materials.

Other suitable thioesters are those having one 3 of nor-cholanic. acids, and related. compounds having substituents as given above the cholenic;

Eso-

series. The nor-cholanic series has the general structure Q Ha,

The thioeste'rs of bisnor-cholanic acids have two less carbon atoms in the side-chain, e. g.:

CH| H16, HvlL-SR:

0 o o -CH;CH:yJ-SR, wait-s11, or -s:a side-chain, regardless of other-nuclear substituents, may be employed. For example, thioesters of 3,11-dihydroxy-bisnor cholenic acid, 3-chloro- (delta -cho1enic acid, 3-acetoxy-='(delta 5) cholenic acid, B-methoxy-(delta 5) -no1:-cholanic' acid, 3,12-diethoxy-nor-cholanic acid, and 3- acetoxy- (delta 5) -bisnor-cholenic acid are entirely satisfactory starting material's.

. A selected steroid acid may be converted to the corresponding thioester by either of two procediireaboth of which proceed through the acid chloride: The first (A)- involves reaction of" the acid" halide e. g1, bromide or'chloride; with amercaptan in pyridine, and the second (3) involves reac'tionof theacid chloride with asuspension" oflead mercaptide in ether, according to the i01 lowing sequence, as illustrated for an unsubsti tutedi acid; a l CH; 0

HiC

HsG

wherein? n is zero, one, or two} and R; is an al cohol' residue; preferably a h-yd roca-rbon radicals Both of 'the given procedureshave proven suit-- able.

Choice of the R radicalin the starting thioester is purely arbitrary, the availability of the mercaptan' or lead mercaptide being the onlylimiting factor-i Rmay thusrbealkyl, e..g., methe yl, ethyl,,propy1, isopropyL. butyl, isobutyl, amyl, n-octy-l, or the; like; cycloalkyl, e. g-., cyclopentyl cyclohexyh cycloalltylalkyl, e.g;, cyclohexylmetm yl;,.aryl, erg, phenyl, naphthyL; or: aralkyl erg-m benzyl. or phenethy-L. Unsaturated aliphatics and cycloaliphtics, or compounds: where. R mayz also bechloroethyl-, nitropheny-Lv aminopropyl i,

4' able:

PROCEDURE A.'MER'APTAN IN PYRIDI'NE' The acid chloride usual-ly inian: organic solvent, such as anhydrous, benzene, is admixed with. at selected'mercaptarr apyridine solution. Equi molar proportions aresatisfactory; but an excess of mercaptan maysometimesbeiemployed to ad, Vantage. reaction rate,- bu-tl is notsusu'ally necessary, as the: reaction occurs readily at room temperature... 'Ilhemeactionproduct may be: worked up withwater and; ether; aqueous portions extractedand the: COmblH8d1th81"1fiyIZ washedi'with: water, dilutei alkaliydilute acid, and agaimwith water; drying the neutral fraction and evaporating; sol vent, the residual oil may be crystallized from a suitable solvent, as g. alcohol,, to yield the de-r sired thioester, usually a stable solid.

PROCEDURE B.LEAD MERCAPTIDE IN ETHER The acid chloride in anhydrousether iii-added to a mixture of ether and selected lead mercaptide, or vice versa. Equimolar proportions are satisfactory; other ratios maybe used if. desired.- The reacticni'miirturei is ailawed t'orstamt withz' occasional swirling, gentle heating if desired; 'Ilhe EXAMPLE 1 .BENZYL 3-AI PH*A,I2#ALPHA- DIACETOXY-NOR-THIOCHOLANA'IZE To l, 5 grams (0.0033 mole) of 3'-a1pha,12 -alpha-,

up as in Proce- Gentle. heating sometimes increasesi After;

diacetoxy-nor-cholanic acid was added 6 milliliters (9.8 grams, 0.082 mole) of purified thionyl chloride (Fieser, Experiments in Organic Chemistry, Part II, Heath and Co., New York, 1941, p. 381). The acid dissolved within five minutes and the solution was allowed to stand, with occasional swirling, at room temperature for one hour. Twenty milliliters of a 1:1 mixture of anhydrous benzene and ether was then added and the whole evaporated to dryness in vacuo at 40 degrees centigrade. This process of treatment with benzeneether was repeated twice to ensure complete removal of excess thionyl chloride.

To the resulting acid chloride dissolved in milliliters of anhydrous benzene was added 0.4 milliliter (0.005 mole) of dry pyridine and 2 milliliters (1.12 grams, 0.009 mole) of benzyl mercaptan, a precipitate soon forming. After standing for twenty-four hours at room temperature, the mixture was diluted with milliliters of water and 15 milliliters of ether, whereafter the precipitate dissolved and the ether-benzene phase was separated. The aqueous portion was extracted with two 15-mil1iliter portions of ether, and the combined ether-benzene layer was washedv with milliliter portions of water, one per cent sodium hydroxide, one per cent hydrochloric acid,

' ether and added to 1.8 grams (0.0055fiio1e) of lead ethyl mercaptide covered with 20 milliliters of anhydrous ether.- The mixture was allowedto stand at room temperature with occasional swirling, the yellow lead mercaptide being gradually replaced by white lead chloride. After twentyfour hours, the solution was filtered and the precipitate washed with milliliters of ether. The combined ether filtrate was washed with 100 milliliters of one per cent sodium hydroxide and 300 milliliters of water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo on the steam bath. The residual oil was dissolved in 50 milliliters of hot alcohol and 10 milliliters of water added. On cooling, an oil separated, taking with it all the color in the solution,- after which crystallization yielded 2.2 grams of material. An. additional 0.32 gram. of "crystals was obtained by crystallizing the oil from alcohol, the total yield being 2.52 grams (51 per cent of the theoretical), M. P. 105-110 degrees centigrade. After three recrystallizations, the melting point was constant at 111-112 degrees centigrade (corn).

Other suitable thioesters which may be employed as starting materials in the method of the present invention are given in the table.

Tabla-Esters of steroid acids Analyses. Per Cent Compound M. P., C. 3 32 2 3; i gfig Carbon Hydrogen Sulfur Calcd. Found Oalcd. Found Calcd. Found ethyl 3-beta-hydroxy-(delta 5)-thiocholenate 108. 5-109. 5 -38. 5 G:|H4zOaS 74. 5 74. 64 10.00 10.07 7. 66 7. 79 ethyl 3-bcta-1ormoxy-(delta 5)-t't i0ChOlBl1flt9 81-82 47. 5 C H gO;S 72. 72. O7 9. 48 9. 61 7. l8 7. 01 ethyl 3-beta-acetoxy-(delta 5)-thiocho1enate 101. 5'l03. 5 40. 9 0 11 0 8". 72. 99 72.92 9. 63 9. 69 6.98 7. 36 isopropyl 3-beta-acet0xy-(delta 5)-thiocholenate 131-133 40. 4 C EhgOzS'.-. 73. 37 73. 39 9. 77 9. 55 6. 6. 81 tert-butyl 3-beta-acetosy-(delta 5)-t'iiocho1enate 169. 5-171 39. 8 CanH-uOaS-.- 73. 42 74. 07 9. 9. 96 6. 56 6. 71 n-liexylEi-beta-acetoxy-(delta SD-thiocholenate. 77. 5-79. 5 35. 4 C::HazO: 37 70 14 00 Si 20 6 6 atijyl-fi-chloro-(delta 5)-tiocholcnate 103. 5-105 30. 4 CaHnOSOL 71. 44 71. 51 9. 46 9. 53 s. 11 4 3, 75 tnyl-a-betagrcetoxy-E-chloro-nor-tliocholanate- 165-168 (31511430 861. 6. 45 s. 32 ethyl 3-beta-acetoxy-(delta 5)-b1snor-th1o cho enate 132-133 -38. 0 0351340015... 72. 18 72. 50 9. 32 9. 13 7. 41 7, 44 ethyl 3-alpha,12-diformoxy thiocholanaten 1ll112 +92. 1 02 11410 8-" 68.25 68. 39 9.00 8.89 6. 51 6. 51 ethyl B-aIpha-iormoxy thiocholanate. 8l-82 +41. 3 021134 0 9" 72. 27 72. 53 9. 89 9. 74 7. l4 7. 23 ethyl S-alpha,l2-diacetoxy-nor-tiiocholanate- 91-91. 5 +96. 0 0201140058". 68. 76 69.07 9. 15 9. 47 6. 33 6, 37 benzyl 3-3.1 pha, 1Z-aIpha-diacetoxy-nor-thiocholanate 6 +9 01411411058--- 71. 79 71. 56 8. 51 8. 79 5. 64 5. 66 phenyl'S-alphaJZ-alpha diacetoxy-nor-thiochol- I agate 6- 47 +99- 7 0x11413055". 71. 44 71. 30 8. 36 8. 04 5. 78 5. 64 pilenyl 3-beta-acetoxy-(delta 5)-t i 0 0]8nflt 5'130 8. 59 6. 29 6. 89 benzyl i-beta a?eto :y-(delta 53-t .i1c.1olenate 8 -86. 5 67 etiyl 3- l]95.18.,P119111,lZ-llglla-tlifOIIl'lOXythlO- ciolanate 128 et 1Y1 341p1c.-21ydroxy-12-alpha-acctoxytnlocholamtcet1yl3-'nethory-(delta 5)- bisnor-thiocholenate 9496 v ethyl 3-benzoyhxy-(delta 5)-thiocholenate 178-182 ethyl tiiodehydrocholate 244-246. 5

1 All M. P.s corrected.

I Rotations taken at approximately 25 C. in chloroform with a 1 cm. tube. 3 Desoxycholic acid is formulated as 3-alpha,l2-alpha, according to the latest evidence (Ann. Rev. Biochem. 15, 162 (1946)).

4 Chlorine analysis.

and finally again with water. The neutral fraction was dried over anhydrous sodium sulfate, the solvent evaporated to dryness in vacuo, and the residual oil crystallized from 50 milliliters of 95 per cent alcohol to give 1.38 grams ('73 per cent) of product, M. P. 147-152 degrees centigrade. After three recrystallizations from alcohol, 123 grams (65.5 per cent) of the benzyl thio ester with a constant melting point of 154-156 degrees centigrade (corr.) was obtained.

EXAMPLE 2.-ETI-IYL 3ALPHA,12-ALPHADI- FQRMOXY-TI-IIOCHOLANATE The acid chloride (prepared from 4.5 grams (0.01 mole) of 3-alpha,12-alpha-diformyl-desoxycholic acid-in the manner described in Example 1) was dissolved in 30 milliliters of anhydrous Desulfurization and reduction of the selected thioester to an alcohol of the formula:

P- (CH2) n-CHzOI-I ts seaweeds-m the reaction vessel after completion. of the" reaction; separated from Rariey type cataly st", and then worked up purification and separation purposes as" desired",

usually by direct crystallization from the solvent employed.

' The following examples are' given to-iI-lustrate the preparation of'theprimary alcohols from the lit no way to be construed asthioesters, butare limiting.

EXAMPLE. 3. 3. A1'.PHA. FORMOXY 2a "A- suspension of 6- grams'of Haney nickel Wisconsi'n) in a solution of 050* gramof" the ethyl thioester of 3-formyl-l'ithocol-ic acid in 25 milli lltersof'absolute-alcoholwas stirred at room tem- The Raney nickel was perature for three hours; separated by filtration, washed with alcohol, the filtrate reduced in volurnerto 20-30 miililitersand diluted with several volumes of' water. The yield of 'S-alpha-fbrmoxw2*l-hydroxy cholan-e was 0142' gram P. 8115 83 degrees centigrade after several recrystallizations from 95% alcohol antiwater: Alpha F .+3O.O* degrees.

EkAMPLE-e .3 BETm-AoETOXY 22.

sin) in 15 milliliters of absolute alcohol in the same manner as given for Example 31- After purification by chromatography and recrystallization from 95% alcohol and water; 231 milligrams,

P. 152453,.5. degrees centigrade, were. obtained.

HYDRO-KY (DELTA 5-) -CHOLENE This; compound was prepared from ethyl 3- beta-acetoxy (delta 5) -thiocholenate: and. found to. melt at 143.5446 degress centigrade. EXAMEPLE c1' 3=' ALPHA-J2 ALPHA- orne. 23 HYDROXY: NOR 'I his.= compound was prepared from 3.0 grams of ethyl 3L1'2-diircetotry-thioenor-cholanate in a? mixture of 200 milliliters of absolute alcohol and 52 milliliters of water; divided into ten equ'al'por tions, which were passed through a column of 10- EXAMPLE 7.,3 BETA,24 mnvnaoxv (DELTA 5) CHOIJENE;

This compound. was prepared from. 5.00. milligrams of ethyl 3-beta-hydroxy-(d.elta 5)-thi'0- cholenate and 6 grams of Pavlic Raney nickel at room temperature in 10.- milliliters of absolute alcohol. The yield was 261 milligrams; M. P. 196-199v degrees centigrade.

EXAMPLE B.-3 ALPHAZI DII-IYDROXY l2 ALPHA-FORMOXY-CHOLANE This compound was prepared from ethyl 3'- alpha, 12-alphadiformoxy-thiocholanate (2.0

grams) and 10 grams of Raney-Wisconsin' nickel catalyst in.10 milliliters of alcohol and 10 milliliters of water; The product was allowed to stand for a short. period of time to allow hydrolysis of the 3-i'ermoxy group to a hydroxy group, and the desired 3-alpha,24-dihydroxy-12a1pha-formoXys I chola-ne (oar-r gram, P. lei-{832d degrees cas tig-rade) separated therefrom.

EXAMPLE 9; 3. ALPHA,2'3 DrnYnnoxY-ra ALPHA ACETOXY-NQRi-CHOLANE This compound was. prepared from ethyl. 3;. alpha -hydroxy 12' alpha. acetoxy nor thiocholanate (1.8 grams). and: 20' grams of Pavhc. Raney nickel 60 milliliters. of" alcohol and" 1,5 milliliters of water- The mixture was; refluxedv 2 hours, 'then cooled, filtered, and. the product; Worked up as described. in Example. 31. The yield of desired product. was. 019.21 gram P- LIZ-L74 degrees centigrade- I An advantage: ofthe. process as. previously outs lined is the possibility ofroductively desul'furizing a. thioeste'r, having. the selected sides-chain length, to a primary alcohol. of correspondingside-chain. length. without. converting. unclean: acyloxy groupsto. hydroxy groups. For exampl starting with. a 3,12-diacyloxy pregnane. deriva:.. tive. of. designated sideschain. length, the reduce. tive. desulfurization converts. the thioester group to a, primary alcohol group without. aflectingthe acyloxy groups. However... when one. or. both; acyl'oxy. groups. are formoxy,. prolongation of. v the. reaction period may be employed, if desired, to

obtain conversion of the formoxy group at position 3 to a hydroxy group. The conversion of the 3-formoxy group to hydroxy may be caused to occur by extending the reaction period or by employing more strenuous reaction conditions.

The; conversion takes place under such conditions, regardless of the acyloxy group at the 12 carbon atom, which in every case. appearsto be. more ing variation of thenuclear acyloxy'groups' as tlie- Q A ACETOXYI 24W j3-hydroxyl may be acylated with; a. difierentgl group-toproduce a compound with: unlike Hymn groups inthe.3 and 1'2p0sitio'ns;

Representative alcohols which may be pres? pared from the corresponding thiojest'ers by. re? ductionwith Raney nickel are as follows:

3-alpha-formoxy-24-hydroxycholane; l -l,. -l l f; r

3-alpha24-dihydrqxy-l2-formoxy-cholane F S-alpha=l-2 alpha-dlacetoxy-23-hydroxy-nor- 3,l2-dibenzoyloXy-24-hydroxy-cholane, 3-beta-ocetoxy-24-hydroxy (delta 5)-cho1en 3 beta-24 dihydroxy-(delta-5).- cholena.

3-alphaf23-dihydroxy-l2-alpha-acetoxy-nor-cholanee 3 alpl1a-12-diacetoxy-23-hydroxy-nor-cholene 3-beta-acetoxy-22-hydroxy-(delta 5)-bisnor-cholene 3-beta-benzoxy-Zi-hydroxy-(delta 5)- cholene wherein P represents a; nucleustselected from the group: consisting of pregnane, pregnene; and pregnadiene nuclei, which-is attached to the s1d;e-'="- chain-in the 20 position; nis seleeted from zerop' converting} an 9 one, and two, and R is a thio-alcohol residue; to a compound of the formula:

wherein P and n have the previously assigned values, by mixing the thioester together with a Raney-type catalyst at a temperature between about zero and 120 degrees centigrade.

2. The process of claim 1, wherein the conversion is with Raney nickel in the presence of an organic solvent.

3. A compound of the formula:

6. 3,24-dihydroxy-12-formoxy-cholane. 7. The process which includes: mixing a compound of the. formula:

i P(CHz)nC-S R wherein P represents a nucleus, selected from the group consisting of pregnane, pregnene, and pregnadiene nuclei, having the side-chain attached in the 20 position; n is selected from zero, one, and two; and R is a thioalcohol residue;

10 with a Haney-type catalyst, in an organic solvent at a temperature between about zero and degrees centigrade; and separating a steroid a1- cohol of the formula wherein P and n have the previously assigned values, from the reaction product.

8. The process of claim 7, wherein the Raneytype catalyst is Raney nickel.

9. The process of claim 7, wherein the starting compound is a thiocholanate.

10. The process of claim 7, wherein the starting compound is a (delta 5) -thiocho1enate.

11. The process of claim 7, wherein the starting compound is a thio-nor-cholanate.

12. The process of claim 7, wherein the starting compound is a S-formoxy-lZ-acyloxy-thiocholanate and the steriod alcohol separated from the reaction product is a 3,24-dihydroXy-12- acyloXy-cholane.

. ROBERT H. LEVIN.

A. VERN McINTOSH, JR.

GEORGE B. SPERO.

REFERENCES CITED The following references are of record in the file of this patent:

Brinks: Jour. Biol. Chem, 162, 695-706 (1946). Wolfram: Jour. Am. Chem. 500., 68, 724-725 (1946). 

1. THE PROCESS WHICH INCLUDES: CONVERTING A COMPOUND OF THE FORMULA: 